CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways

Proteins possessing the caspase recruitment domain (CARD) motif have been i mplicated in pathways leading to activation of caspases or NF-kappaB in the context of apoptosis or inflammation, respectively. Here we report the ide ntification of a novel protein, CARDINAL, that contains a CARD motif and al so exhibits a high degree of homology to the C terminus of DEFCAP/NAC, a re cently described member of the Apaf-1/Nod-1 family. In contrast with the ma jority of CARD proteins described to date, CARDINAL failed to promote apopt osis or NF-kappaB activation. Rather, CARDINAL potently suppressed NF-kappa B activation associated with overexpression of TRAIL-R1, TRAIL-R2, RIP, RIC K, Bcl10, and TRADD, or through ligand-induced stimulation of the interleuk in-1 or tumor necrosis factor receptors. Co-immunoprecipitation experiments revealed that CARDINAL interacts with the regulatory subunit of the I kapp aB kinase (IKK) complex, IKK gamma (NEMO), providing a molecular basis for CARDINAL function. Thus, CARDINAL is a novel regulator of NF-kappaB activat ion in the context of pro-inflammatory signals.